Clozapine is the prototypical "atypical" antipsychotic agent. This therapeutic provides relief from the delusional and depressive symptoms of schizophrenia without producing the severe side-effects which characterized the typical antipsychotics. Recent advances in the molecular biology of monoaminergic receptors has revealed "inverse agonist" properties of atypical drugs, such as clozapine, at the serotonin 5-HT2A receptor. Inverse agonism affords drugs the ability to block ligand-independent activity of receptors by destabilizing the active conformation of the receptor protein. We propose to use recombinant DNA technology to produce a constitutively active form of the human 5-HT2A receptor which will be used to screen for specific novel 5- HT2A receptor inverse agonists. Site-directed mutagenesis will be employed to substitute specific amino acids involved in constraining the wild type human 5-HT2A receptor in the inactive conformation. The resulting constitutively active 5-HT2A receptor will be employed to screen a small molecule chemical library to directly identify 5-HT2A inverse agonists. Identified molecules will be further modified chemically to produce high potency 5-HT2A receptor inverse agonists. The overall purpose of this proposal is to identify potent molecules which will be further developed as potential novel antipsychotic agents.